US6511649B1ExpiredUtility
Vitronectin receptor antagonist pharmaceuticals
Priority: Dec 18, 1998Filed: Jun 21, 2000Granted: Jan 28, 2003
Est. expiryDec 18, 2018(expired)· nominal 20-yr term from priority
A61K 49/10A61K 49/0002C07D 401/14A61K 51/0455A61K 49/085A61K 51/0459C07D 401/12A61K 49/223A61K 51/0497A61K 49/04
86
PatentIndex Score
19
Cited by
143
References
46
Claims
Abstract
The present invention describes novel compounds of the formula:useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The present invention further provides novel compounds useful for imaging atherosclerosis, restenosis, cardiac ischemia, and myocardial reperfusion injury. The present invention still further provides novel compounds useful for the treatment of rheumatoid arthritis. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
Claims
exact text as granted — not AI-modifiedWhat is claimed is described below:
1. A therapeutic radiopharmaceutical composition comprising at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a radiopharmaceutical comprising:
(a) a metal;
(b) a chelator capable of chelating the metal;
(c) a targeting moiety;
(d) 0-1 linking groups between the targeting moiety and chelator;
wherein the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis.
2. A therapeutic radiopharmaceutical composition according to claim 1 , wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
3. A therapeutic radiopharmaceutical composition according to claim 1 , wherein radiosensitizer agent is selected from the group consisting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
4. A method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical comprising:
(a) a metal;
(b) a chelator capable of chelating the metal
(c) a targeting moiety; and
(d) 0-1 linking groups between the targeting moiety and chelator;
wherein the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis; and the metal is a radioisotope selected from the group: 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 Y, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 Cu, 105 Rh, 111 Ag, and 192 Ir, or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof.
5. A method of treating cancer according to claim 4 , wherein the administration is by injection or infusion.
6. A method according to claim 4 wherein administering the therapeutic radiopharmaceutical and agent is concurrent.
7. A method according to claim 4 wherein administering the therapeutic radiopharmaceutical and agent is sequential.
8. A method according to claim 4 wherein the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate,thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, and neuroblastomas.
9. A method according to claim 4 wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
10. A method according to claim 4 wherein the radiosensitizer agent is selected from the group consisting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
11. A kit for treating cancer, comprising at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a compound comprising:
a) a chelator;
b) a targeting moiety;
c) 0-1 linking groups between the targeting moiety and chelator;
wherein the targeting moiety is a quinolone non-peptide that binds to a receptor that is upregulated during angiogenesis.
12. Kit for treating cancer according to claim 11 , wherein the compound is of the formula:
(Q) d —L n —C h or (Q) d —L n —(C h ) d′
wherein, Q is a compound of Formula (II):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
R 1e is selected from:
A e is —CH 2 — or —N(R 10e )—;
A 1e and B e are independently —CH 2 — or —N(R 10e )—;
D e is —N(R 10e )— or —S—;
E e —F e is —C(R 2e )═C(R 3e )— or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is —C(R 2e )— or —N—;
K e , L e and M e are independently —C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl (C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —(CH 2 ) n e N(R 12 )(CH 2 ) m e —, —NH(CH 2 ) n e —, —(CH 2 ) n e C(═O)(CH 2 ) m e —, —(CH 2 ) n e S(O) p e (CH 2 ) m e —, —(CH 2 ) n e NHNH(CH 2 ) m e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, —C(═O)N(R 10e )—, and —N(R 10e )S(O) p e —;
G e is N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group is substituted by R 8e and by R 9e :
R 8e and R 9e are independently selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17 R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ,
C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
hydroxy, nitro, —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 3 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from: H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, (C 1 -C 10 alkyl)carbonyl, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C 1 -C 6 alkyl, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 3 -C 7 cycloalkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, aryl(C 1 -C 4 alkoxy)carbonyl, C 1 -C 6 alkylsulfonyl, and arylsulfonyl;
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , —C(═O)NHSO 2 NHR 18be , —SO 2 R 18ae , —SO 2 N(R 18be ) 2 , and —SO 2 NHC(═O)OR 18be ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
Y e is selected from: —COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
d′ is 1-100;
L n is a linking group having the formula:
((W) h —(CR 6 R 7 ) g ) x —(Z) k —((CR 6a R 7a ) g′ —(W) h′ ) x′ ;
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , OH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
R 12 is a bond to C h ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, and 2;
g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
x is selected from 0, 1, 2, 3, 4, and 5;
x′ is selected from 0, 1, 2, 3, 4, and 5;
C h is a metal bonding unit having a formula selected from the group:
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 15 and R 16 are each independently selected from the group: a bond to L n , —OH, C 1 -C 10 alkyl substituted with 0-3 R 17 , C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6 alkyl, phenyl, benzyl, C 1 -C 6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R 20 and R 21 are independently selected from the group: H, C 1 -C 10 alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10 1-alkene substituted with 0-3 R 23 , C 2 -C 10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10 carbocycle substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, R 24 , C 1 -C 10 alkyl substituted with 0-3 R 24 , C 2 -C 10 alkenyl substituted with 0-3 R 24 , C 2 -C 10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10 carbocycle substituted with 0-3 R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
a and b indicate the positions of optional double bonds and n is 0 or 1;
R 24 is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3 +, —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, —SO 2 R 25a , —SR 25 , —S(═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,
R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
13. A kit according to claim 12 wherein said kit comprises a plurality of separate containers, wherein at least one of said containers contains one or more agents selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and another of said containers contains a compound of formula:
(Q) d —L n —C h or (Q) d —L n —(C h ) d′
wherein, Q is a compound of Formula (II):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
A e is —CH 2 — or —N(R 10e )—;
A 1e and B e are independently —CH 2 — or —N(R 10e )—;
D e is —N(R 10e )— or —S—;
E e —F e is —C(R 2e )═C(R 3e )— or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is —C(R 2e )— or —N—;
K e , L e and M e are independently —C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —(CH 2 ) n e N(R 12 )(CH 2 ) m e —, —NH(CH 2 ) n e —, —(CH 2 ) n e C(═O)(CH 2 ) m e —, —(CH 2 ) n e S(O) p e (CH 2 ) m e —, —(CH 2 ) n e NHNH(CH 2 ) m e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, —C(═O)N(R 10e )—, and —N(R 10e )S(O) p e —;
G e is N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group is substituted by R 8e and by R 9e :
R 8e and R 9e are independently selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17 R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ,
C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
hydroxy, nitro, —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 3 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from: H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, (C 1 -C 10 alkyl)carbonyl, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C 1 -C 6 alkyl, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 3 -C 7 cycloalkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, aryl(C 1 -C 4 alkoxy)carbonyl, C 1 -C 6 alkylsulfonyl, and arylsulfonyl;
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , —C(═O)NHSO 2 NHR 18be , —SO 2 R 18ae , —SO 2 N(R 18be ) 2 , and —SO 2 NHC(═O)OR 18be ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
Y e is selected from: —COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
d′ is 1-100;
L n is a linking group having the formula:
((W) h —(CR 6 R 7 ) g ) x —(Z) k —((CR 6a R 7a ) g′ —(W) h′ ) x′ ;
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , OH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
R 12 is a bond to C h ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, and 2;
g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
x is selected from 0, 1, 2, 3, 4, and 5;
x′ is selected from 0, 1, 2, 3, 4, and 5;
C h is a metal bonding unit having a formula selected from the group:
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 15 and R 16 are each independently selected from the group: a bond to L n , —OH, C 1 -C 10 alkyl substituted with 0-3 R 17 , C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6 alkyl, phenyl, benzyl, C 1 -C 6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R 20 and R 21 are independently selected from the group: H, C 1 -C 10 alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10 1-alkene substituted with 0-3 R 23 , C 2 -C 10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10 carbocycle substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, R 24 , C 1 -C 10 alkyl substituted with 0-3 R 24 , C 2 -C 10 alkenyl substituted with 0-3 R 24 , C 2 -C 10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10 carbocycle substituted with 0-3 R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
a and b indicate the positions of optional double bonds and n is 0 or 1;
R 24 is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3 +, —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, SO 2 R 25a , —SR 25 , —S(═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,
R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
14. A kit according to claim 12 , wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
15. A kit according to claim 12 , wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, and lisuride.
16. A kit according to claim 12 wherein the chemotherapeutic agent is selected from the group consisting of oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, and formestane.
17. A kit according to claim 12 wherein the chemotherapeutic agent is selected from the group consisting of interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
18. A kit according to claim 12 , wherein radiosensitizer agent is selected from the group consisting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol.
19. A kit according to claim 12 , wherein Q is a compound of Formula (IV):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, and —C(═O)N(R 10e )—;
G e is N or CR 19e ;
R 8e is selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 9e is selected from: C 1 -C 10 alkyl substituted with 0-1 R 6e , C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 1 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4; and
p e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1 and —COR 20e in Formula (IV) is in the range of 8-14;
d is selected from 1, 2, 3, 4, and 5;
d′ is 1-50;
W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-1 R 10 , C 3-10 cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, C 1 -C 5 alkyl substituted with 0-1 R 10 , aryl substituted with 0-1 R 10 , benzyl substituted with 0-1 R 10 , and C 1 -C 5 alkoxy substituted with 0-1 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
k is 0 or 1;
s is selected from 0, 1, 2, 3, 4, and 5;
s′ is selected from 0, 1, 2, 3, 4, and 5;
s″ is selected from 0, 1, 2, 3, 4, and 5;
t is selected from 0, 1, 2, 3, 4, and 5;
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C 1 -C 6 alkyl;
R 20 and R 21 are independently selected from the group: H, C 1 -C 5 alkyl, —CO 2 R 25 , C 2 -C 5 1-alkene substituted with 0-3 R 23 , C 2 -C 5 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, and R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 24 is independently selected at each occurrence from the group: —CO 2 R 25 , —C(═O)N(R 25 ) 2 , —CH 2 OR 25 , —OC(═O)R 25 , —OR 25 , —SO 3 H, —N(R 25 ) 2 , and —OCH 2 CO 2 H; and,
R 25 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
20. A kit according to claim 12 , wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, and —NHC(═O)(CH 2 ) n e ;
G e is N or CR 19e ;
R 8e is H;
R 9e is selected from: H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 4 alkyl)carbonyl, aryl(C 1 -C 4 alkyl), heteroaryl(C 1 -C 4 alkyl), CONR 18ae R 20e , So 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, aryl, (C 3 -C 6 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 4 alkyl substituted with 0-2 R 6e ;
R 6e is selected from: H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 4 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 11e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, C 1 -C 4 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 4 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, and heteroaryl(C 1 -C 4 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 4 alkyl, (C 1 -C 4 alkyl)carbonyl, (C 1 -C 4 alkoxy)carbonyl, phenyl(C 1 -C 4 alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl(C 1 -C 4 alkoxy)carbonyl, wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4;
p e is 0-2;
C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 4 , and A 6 are each N;
A 3 , A 5 , and A 8 are each OH;
A 7 is a bond to L n or NH-bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 3 and A 4 are each N;
A 5 , A 6 and A 8 are each OH;
A 7 is a bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is NH 2 or N═C(R 20 )(R 21 );
E is a bond;
A 2 is NHR 13 ;
R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
R 17 is selected from a bond to L n , C(═O)NHR 18 and C(═O)R 18 ;
R 18 is a bond to L n ;
R 24 is selected from the group: —CO 2 R 25 , —OR 25 , —SO 3 H, and —N(R 25 ) 2 ; and,
R 25 is independently selected at each occurrence from the group: hydrogen and methyl.
21. A kit according to claim 12 , wherein:
Q is selected from the group:
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6,dichlorophenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid, and
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid.
22. A kit according to claim 11 , wherein the compound is selected from the group:
2-(((4-(4-(((3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid;
3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoic acid;
2-(((4-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic;
3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid;
3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid;
3-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid;
2-(2-aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid;
2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid;
2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid conjugate; and
2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid;
or a pharmaceutically acceptable salt form thereof.
23. A kit according to claim 12 , wherein the kit further comprises one or more ancillary ligands and a reducing agent.
24. A kit according to claim 23 , wherein the ancillary ligands are tricine and TPPTS.
25. A kit according to claim 23 , wherein the reducing agent is tin(II).
26. A therapeutic radiopharmaceutical composition according to claim 1 , wherein the metal is selected from the group: 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 Y, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 Cu, 105 Rh, 111 Ag, and 192 Ir; and the linking group is present between the non-peptide targeting moiety and chelator.
27. A therapeutic radiopharmaceutical composition according to claim 26 , wherein the receptor is α v β 3 or α v β 5 .
28. A therapeutic radiopharmaceutical composition according to claim 1 , wherein the radiopharmaceutical comprises:
a) a metal selected from the group 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 Y, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 CU, 105 Rh, 111 Ag, and 192 Ir; and
b) a compound of the formula:
(Q) d —L n —C h or (Q) d —L n —(C h ) d′
wherein, Q is a compound of Formula (II):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
A e is —CH 2 — or —N(R 10e )—;
A 1e and B e are independently —CH 2 — or —N(R 10e )—;
D e is —N(R 10e )— or —S—;
E e —F e is —C(R 2e )═C(R 3e )— or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is —C(R 2e )— or —N—;
K e , L e and M e are independently —C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —(CH 2 ) n e N(R 12 )(CH 2 ) m e —, —NH(CH 2 ) n e —, —(CH 2 ) n e C(═O)(CH 2 ) m e —, —(CH 2 ) n e S(O) p e (CH 2 ) m e —, —(CH 2 ) n e NHNH(CH 2 ) m e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, —C(═O)N(R 10e )—, and —N(R 10e )S(O) p e —;
G e is N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group is substituted by R 8e and by R 9e :
R 8e and R 9e are independently selected from:
H, CO 2 R 18be , C(═O)R 18be , CONR 17 R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ,
C 1 -C 10 alkoxy substituted with 0-2 R 7e , hydroxy, nitro, —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 3 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl) , CONR 18ae R 20e , SO 2 R 18e , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, (C 1 -C 10 alkyl)carbonyl, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C 1 -C 6 alkyl, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 3 -C 7 cycloalkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, aryl(C 1 -C 4 alkoxy)carbonyl, C 1 -C 6 alkylsulfonyl, and arylsulfonyl;
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O) OR 18ae , —C(═O)NHSO 2 NHR 18be , —SO 2 R 18ae , —SO 2 N(R 18be ) 2 , and —SO 2 NHC(═O)OR 18be ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
Y e is selected from: —COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-;
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
d′ is 1-100;
L n is a linking group having the formula:
((W) h —(CR 6 R 7 ) g ) x —(Z) k —((CR 6a R 7a ) g′ —(W) h′ ) x′ ;
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3 -C 10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , OH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
R 12 is a bond to C h ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, and 2;
g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
x is selected from 0, 1, 2, 3, 4, and 5;
x′ is selected from 0, 1, 2, 3, 4, and 5;
C h is a metal bonding unit having a formula selected from the group:
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 15 and R 16 are each independently selected from the group: a bond to L n , —OH, C 1 -C 10 alkyl substituted with 0-3 R 17 , C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6 alkyl, phenyl, benzyl, C 1 -C 6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R 20 and R 21 are independently selected from the group: H, C 1 -C 10 alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10 1-alkene substituted with 0-3 R 23 , C 2 -C 10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10 carbocycle substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, R 24 , C 1 -C 10 alkyl substituted with 0-3 R 24 , C 2 -C 10 alkenyl substituted with 0-3 R 24 , C 2 -C 10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10 carbocycle substituted with 0-3 R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
a and b indicate the positions of optional double bonds and n is 0 or 1;
R 24 is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3 + , —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, —SO 2 R 25a , —SR 25 , —S(═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,
R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
29. A therapeutic radiopharmaceutical composition according to claim 28 , wherein Q is a compound of Formula (IV):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, (CH 2 ) n e O(CH 2 ) m e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, and —C(═O)N(R 10e )—;
G e is N or CR 19e ;
R 8e is selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 9e is selected from: C 1 -C 10 alkyl substituted with 0-1 R 6e , C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 1 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , So 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4; and
p e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1 and —COR 20e in Formula (IV) is in the range of 8-14;
d is selected from 1, 2, 3, 4, and 5;
d′ is 1-50;
W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-1 R 10 , C 3 -C 10 cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, C 1 -C 5 alkyl substituted with 0-1 R 10 , aryl substituted with 0-1 R 10 , benzyl substituted with 0-1 R 10 , and C 1 -C 5 alkoxy substituted with 0-1 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
k is 0 or 1;
s is selected from 0, 1, 2, 3, 4, and 5;
s′ is selected from 0, 1, 2, 3, 4, and 5;
s″ is selected from 0, 1, 2, 3, 4, and 5;
t is selected from 0, 1, 2, 3, 4, and 5;
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C 1 -C 6 alkyl;
R 20 and R 21 are independently selected from the group: H, C 1 -C 5 alkyl, —CO 2 R 25 , C 2 -C 5 1-alkene substituted with 0-3 R 23 , C 2 -C 5 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, and R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 24 is independently selected at each occurrence from the group: —CO 2 R 25 , —C(═O)N(R 25 ) 2 , —CH 2 OR 25 , —OC(═O)R 25 , —OR 25 , —SO 3 H, —N(R 25 ) 2 , and —OCH 2 CO 2 H; and,
R 25 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
30. A therapeutic radiopharmaceutical composition according to claim 28 , wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 1 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, and —NHC(═O)(CH 2 ) n e ;
G e is N or CR 19e ;
R 8e is H;
R 9e is selected from:
H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 4 alkyl)carbonyl, aryl(C 1 -C 4 alkyl), heteroaryl(C 1 -C 4 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, aryl, (C 3 -C 6 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 4 alkyl substituted with 0-2 R 6e ;
R 6e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 4 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 11e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, C 1 -C 4 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 4 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, and heteroaryl(C 1 -C 4 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 4 alkyl, (C 1 -C 4 alkyl)carbonyl, (C 1 -C 4 alkoxy)carbonyl, phenyl(C 1 -C 4 alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl(C 1 -C 4 alkoxy)carbonyl, wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4;
p e is 0-2;
C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 4 , and A 6 are each N;
A 3 , A 5 , and A 8 are each OH;
A 7 is a bond to L n or NH-bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 3 and A 4 are each N;
A 5 , A 6 and A 8 are each OH;
A 7 is a bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is NH 2 or N═C(R 20 )(R 21 );
E is a bond;
A 2 is NHR 13 ;
R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
R 17 is selected from a bond to L n , C(═O)NHR 18 and C(═O)R 18 ; R 18 is a bond to L n ;
R 24 is selected from the group: —CO 2 R 25 , —OR 25 , —SO 3 H, and —N(R 25 ) 2 ; and,
R 25 is independently selected at each occurrence from the group: hydrogen and methyl.
31. A therapeutic radiopharmaceutical composition according to claim 28 , wherein Q is selected from the group:
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6,dichlorophenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid, and
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid.
32. A therapeutic radiopharmaceutical composition according to claim 28 , wherein the radioisotope is 153 Sm.
33. A therapeutic radiopharmaceutical composition according to claim 28 , wherein the radioisotope is 177 Lu.
34. A therapeutic radiopharmaceutical composition according to claim 1 , wherein the radiopharmaceutical is selected from the group:
35. A therapeutic radiopharmaceutical composition according to claim 28 , wherein the radioisotope is 90 Y.
36. A therapeutic radiopharmaceutical composition according to claim 1 , wherein the radiopharmaceutical is selected from the group;
37. A method according to claim 4 , wherein the targeting moiety is a quinolone non-peptide and the receptor is α v β 3 or α v β 5 .
38. A method according to claim 4 , wherein the therapeutic radiopharmaceutical comprises:
a) a radioisotope selected from the group: 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 U, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 Cu, 105 Rh, 111 Ag, and 192 Ir; and
b) a compound of the formula:
(Q) d —L n —C h or (Q) d —L n —(C h ) d′
wherein, Q is a compound of Formula (II):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
A e is —CH 2 — or —N(R 10e )—;
A 1e and B e are independently —CH 2 — or —N(R 10e )—;
D e is —N(R 10e )— or —S—;
E e —F e is —C(R 2e )═C(R 3e )— or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is —C(R 2e )— or —N—;
K e , L e and M e are independently —C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —(CH 2 ) n e N(R 12 )(CH 2 ) m e —, —NH(CH 2 ) n e —, —(CH 2 ) n e C(═O)(CH 2 ) m e —, —(CH 2 ) n e S(O) p e (CH 2 ) m e —, —(CH 2 ) n e NHNH(CH 2 ) m e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, —C(═O)N(R 10e )—, and —N(R 10e )S(O) p e ;
G e is N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group is substituted by R 8e and by R 9e :
R 8e and R 9e are independently selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17 R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ,
C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
hydroxy, nitro, N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 3 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, (C 1 -C 10 alkyl)carbonyl, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C 1 -C 6 alkyl, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 3 -C 7 cycloalkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, aryl(C 1 -C 4 alkoxy)carbonyl, C 1 -C 6 alkylsulfonyl, and arylsulfonyl;
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , —C(═O)NHSO 2 NHR 18be , —SO 2 R 18ae , —SO 2 N(R 18be ) 2 , and —SO 2 NHC(═O)OR 18be ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to Lr, aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
Y e is selected from: —COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
d′ is 1-100;
L n is a linking group having the formula:
((W) h —(CR 6 R 7 ) g ) x —(Z) k —((CR 6a R 7a ) g′ —(W) h′ ) x′ ;
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , OH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and C and substituted with 0-1 R 12 , C 3 -C 10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
R 12 is a bond to C h ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, and 2;
g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
x is selected from 0, 1, 2, 3, 4, and 5;
x′ is selected from 0, 1, 2, 3, 4, and 5;
C h is a metal bonding unit having a formula selected from the group:
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17, C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 15 and R 16 are each independently selected from the group: a bond to L n , —OH, C 1 -C 10 alkyl substituted with 0-3 R 17 , C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6 alkyl, phenyl, benzyl, C 1 -C 6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R 20 and R 21 are independently selected from the group: H, C 1 -C 10 alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10 1-alkene substituted with 0-3 R 23 , C 2 -C 10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10 carbocycle substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, R 24 , C 1 -C 10 alkyl substituted with 0-3 R 24 , C 2 -C 10 alkenyl substituted with 0-3 R 24 , C 2 -C 10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10 carbocycle substituted with 0-3 R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
a and b indicate the positions of optional double bonds and n is 0 or 1;
R 24 is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3 + , —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, —SO 2 R 25a , —SR 25 , S(═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,
R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
39. A method according to claim 38 , wherein:
Q is a compound of Formula (IV):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 1 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —(CH 2 ) n e O(CH 2 ) m e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, —NHC(═O)(CH 2 ) n e —, and —C(═O)N(R 10e )—;
G e is N or CR 19e ;
R 8e is selected from: H, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , C 1 -C 10 alkyl substituted with 0-1 R 6e , C 2 -C 10 alkenyl substituted with 0-1 R 6e , C 2 -C 10 alkynyl substituted with 0-1 R 6e , C 3 -C 8 cycloalkyl substituted with 0-1 R 6e , C 5 -C 6 cycloalkenyl substituted with 0-1 R 6e , (C 1 -C 10 alkyl)carbonyl, C 3 -C 10 cycloalkyl(C 1 -C 4 alkyl)-, phenyl substituted with 0-3 R 6e , naphthyl substituted with 0-3 R 6e ,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 9e is selected from: C 1 -C 10 alkyl substituted with 0-1 R 6e , C 1 -C 10 alkoxy substituted with 0-2 R 7e ,
H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 6 alkyl)carbonyl, aryl(C 1 -C 6 alkyl), heteroaryl(C 1 -C 6 alkyl), CONR 18ae R 20e , SO 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, aryl, (C 3 -C 11 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 10 alkyl substituted with 0-2 R 6e ;
R 11e is selected from: H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, C 1 -C 6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae , C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from: C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, (C 3 -C 11 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , —C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4; and
p e is 0-2;
with the following proviso: n e and m e are chosen such that the number of atoms connecting R 1 and —COR 20e in Formula (IV) is in the range of 8-14;
d is selected from 1, 2, 3, 4, and 5;
d′ is 1-50;
W is independently selected at each occurrence from the group: O, NH, NHC(═O), C(═O)NH, NR 8 C(═O), C(═O)N R 8 , C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-1 R 10 , C 3-10 cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 10 ;
R 6 , R 6a , R 7 , R 7a , and R 8 are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, C 1 -C 5 alkyl substituted with 0-1 R 10 , aryl substituted with 0-1 R 10 , benzyl substituted with 0-1 R 10 and C 1 -C 5 alkoxy substituted with 0-1 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
k is 0 or 1;
s is selected from 0, 1, 2, 3, 4, and 5;
s′ is selected from 0, 1, 2, 3, 4, and 5;
s″ is selected from 0, 1, 2, 3, 4, and 5;
t is selected from 0, 1, 2, 3, 4, and 5;
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C 1 -C 6 alkyl;
R 20 and R 21 are independently selected from the group: H, C 1 -C 5 alkyl, —CO 2 R 25 , C 2 -C 5 1-alkene substituted with 0-3 R 23 , C 2 -C 5 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, and R 24 ;
alternatively, R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N. S, and O;
R 24 is independently selected at each occurrence from the group: —CO 2 R 25 , —C(═O)N(R 25 ) 2 , —CH 2 OR 25 , —OC(═O)R 25 , —OR 25 , —SO 3 H, —N(R 25 ) 2 , and —OCH 2 CO 2 H; and,
R 25 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
40. A method according to claim 38 , wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from: H, C 1 -C 4 alkoxy, NR 11e R 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R 7e ,
alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 and NO 2 ;
R 2ae is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl), aryl, aryl(C 1 -C 4 alkyl)-, (C 2 -C 7 alkyl)carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy)carbonyl, C 3 -C 7 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 6 alkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, arylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl, and C 3 -C 7 cycloalkylcarbonyloxy(C 1 -C 4 alkoxy)carbonyl;
R 7e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, aryl(C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , and N(R 11e )R 12e ;
U e is selected from: —(CH 2 ) n e —, —NH(CH 2 ) n e —, —N(R 10e )C(═O)—, and —NHC(═O)(CH 2 ) n e ;
G e is N or CR 19e ;
R 8e is H;
R 9e is selected from:
H, nitro, N(R 11e )R 12e , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , hydroxy, OR 22e , —N(R 10e )R 11e , —N(R 16e )R 17e , aryl(C 0 -C 4 alkyl)carbonyl, aryl(C 1 -C 4 alkyl), heteroaryl(C 1 -C 4 alkyl), CONR 18ae R 20e , So 2 R 18ae , and SO 2 NR 18ae R 20e ,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 10e is selected from: H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, aryl, (C 3 -C 6 cycloalkyl)methyl, aryl(C 1 -C 4 alkyl), and C 1 -C 4 alkyl substituted with 0-2 R 6e ;
R 6e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 4 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p R 11e , SO 2 NR 10e R 11e ,
aryl substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) m e Me, and —NMe 2 ,
aryl(C 1 -C 4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, CF 3 , S(O) p e Me, and —NMe 2 , and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7e ;
R 11e is selected from: H, hydroxy, C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, C 1 -C 4 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl), adamantylmethyl, and C 1 -C 4 alkyl substituted with 0-2 R 4e ;
R 4e is selected from: H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 4 alkyl)-, aryl, heteroaryl, aryl(C 1 -C 4 alkyl)-, and heteroaryl(C 1 -C 4 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, F, Cl, Br, CF 3 , and NO 2 ,
R 12e is selected from: H, C 1 -C 4 alkyl, (C 1 -C 4 alkyl)carbonyl, (C 1 -C 4 alkoxy)carbonyl, phenyl(C 1 -C 4 alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl (C 1 -C4 alkoxy)carbonyl, wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from: —C(═O)OR 18ae —C(═O)R 18be , —C(═O)N(R 18be ) 2 , —SO 2 R 18ae , and —SO 2 N(R 18be ) 2 ;
R 17e is selected from: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl, aryl(C 1 -C 6 alkyl)-, and heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)- optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is H or R 18ae ;
R 19e is selected from: H, halogen, CF 3 , CO 2 H, CN, NO 2 , —NR 11e R 12e , OCF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 4 alkyl)-, aryl(C 1 -C 4 alkyl)-, C 1 -C 6 alkoxy, C 1 -C 4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO 2 —, heteroaryl, and heteroaryl-SO 2 —, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, and C 1 -C 3 alkoxy;
R 20e is selected from: hydroxy, C 1 -C 6 alkyloxy, C 3 -C 6 cycloalkyloxy, aryloxy, aryl(C 1 -C 4 alkyl)oxy, C 2 -C 10 alkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 2 -C 10 alkoxycarbonyl(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyloxy(C 1 -C 2 alkyl)oxy-, C 3 -C 10 cycloalkoxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyl(C 1 -C 2 alkyl)oxy-, aryloxycarbonyloxy(C 1 -C 2 alkyl)oxy-, arylcarbonyloxy(C 1 -C 2 alkyl)oxy-, C 1 -C 5 alkoxy(C 1 -C 5 alkyl)carbonyloxy(C 1 -C 2 alkyl)oxy, (5-(C 1 -C 5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R 10e )(R 11e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)methyl, aryl, aryl(C 1 -C 4 alkyl)-, and C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from: —C(═O)—R 18be , C(═O)N(R 18be ) 2 , —C(═O)NHSO 2 R 18ae , —C(═O)NHC(═O)R 18be , —C(═O)NHC(═O)OR 18ae , and —C(═O)NHSO 2 NHR 18be ;
m e is 0-2;
n e is 0-4;
p e is 0-2;
C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 4 , and A 6 are each N;
A 3 , A 5 , and A 8 are each OH;
A 7 is a bond to L n or NH-bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 3 and A 4 are each N;
A 5 , A 6 and A 8 are each OH;
A 7 is a bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is NH 2 or N═C(R 20 )(R 21 )
E is a bond;
A 2 is NHR 13 ;
R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
R 17 is selected from a bond to L n , C(═O)NHR 18 and C((═O)R 18 ;
R 18 is a bond to L n ;
R 24 is selected from the group: —CO 2 R 25 , —OR 25 , —SO 3 H, and —N(R 25 ) 2 ; and,
R 25 is independently selected at each occurrence from the group: hydrogen and methyl.
41. A method according to claim 38 , wherein:
Q is selected from the group:
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(pyridin-2-ylamine)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6,dichlorophenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid, and
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid.
42. A method according to claim 38 , wherein the radioisotope is 153 Sm.
43. A method according to claim 38 , wherein the radioisotope is 177 Lu.
44. A method according to claim 4 , wherein the radiopharmaceutical is selected from the group:
45. A method according to claim 38 , wherein the radioisotope is 90 Y.
46. A method according to claim 4 , wherein the radiopharmaceutical is selected from the group;Cited by (0)
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